Evolution of regulation and function of dual coding CDKN2A: implications in development, physiology and cancer
Supervisors
Nuno Morais
GIMM,1st supervisor
Manuel Irimia
CRG,2nd supervisor
Objectives
Explore the functional implications of tissue-specific expression, regulatory mechanisms, and evolutionary dynamics of dual-coding gene CDKN2A to understand its role in development, physiology, and disease by: i) investigating the evolutionary dynamics of p16 and ARF expression across vertebrates; ii) characterising the regulatory mechanisms controlling p16 and ARF expression in human and murine tissues; iii) analysing omics data to assess the contributions of p16 and ARF to tumour suppression and oncogene-induced senescence.
Methodology
The DC will employ a broad set of computational biology approaches, namely associated with comparative genomics and transcriptomics, evolutionary modelling, variant calling, and analyses of epigenomic and transcriptomic data, and associated phenotypic (often clinical) metadata. There will be a strong focus on critical thinking, quantitative rigour, transparency, reproducibility and intelligibility. The DC will therefore also use methods for development of open-source interactive apps for data sharing and visualisation.
Required Skills
Good understanding of cell and molecular biology, genetics and genomics.
Programming skills.
Strong quantitative knowledge, namely in algebra and statistics.
Expected Results
This project will yield insights into the evolutionary and regulatory mechanisms of CDKN2A, clarifying the distinct roles of p16 and ARF in development, senescence and cancer. Findings may inform targeted cancer therapies by identifying CDKN2A-related pathways and markers relevant for tumour suppression and senescence.
Planned Secondments
CRG (Irimia) in year 3 (2 months) to learn about alternative splicing and isoform regulation and evolution.
CRG (Dias) in year 3 (2 week) to receive training on machine learning.
ICR (Graham) in year 3 (1 week) to learn about tumour evolution research and adaptive therapies.
Enrolment in doctoral programs
The DC will enroll in GIMM’s Biology and Biomedicine PhD Program and will be registered in the PhD Programme of
the Lisbon Academic Medical Centre (CAML), hosted by the Faculty of Medicine at the University of Lisbon.
References
1. Schneider, A. L., Martins-Silva, R., Kaizeler, A., Saraiva-Agostinho, N., & Barbosa-Morais, N. L. (2024). voyAGEr, a free web interface for the analysis of age-related gene expression alterations in human tissues. eLife, 12, RP88623. https://doi.org/10.7554/eLife.88623
2. Ascensão-Ferreira, M., Martins-Silva, R., Saraiva-Agostinho, N., & Barbosa-Morais, N. L. (2024). betAS: intuitive analysis and visualization of differential alternative splicing using beta distributions. RNA, 30(4), 337–353. https://doi.org/10.1261/rna.079764.123
3. de Almeida, B. P., Vieira, A. F., Paredes, J., Bettencourt-Dias, M., & Barbosa-Morais, N. L. (2019). Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome. PLoS Computational Biology, 15(3), e1006832. https://doi.org/10.1371/journal.pcbi.1006832
4. Saraiva-Agostinho, N., & Barbosa-Morais, N. L. (2019). psichomics: graphical application for alternative splicing quantification and analysis. Nucleic Acids Research, 47(2), e7. https://doi.org/10.1093/nar/gky888
5. Barbosa-Morais, N. L., Irimia, M., Pan, Q., Xiong, H. Y., Gueroussov, S., Lee, L. J., Slobodeniuc, V., Kutter, C., Watt, S., Colak, R., Kim, T., Misquitta-Ali, C. M., Wilson, M. D., Kim, P. M., Odom, D. T., Frey, B. J., & Blencowe, B. J. (2012). The evolutionary landscape of alternative splicing in vertebrate species. Science, 338(6114), 1587–1593. https://doi.org/10.1126/science.1230612